Evaluation of Water-Related T₂ Relaxation Behavior in Hot-Melt Extruded Clotrimazole/PVPVA Solid Dispersions Using...

Hot-melt extrusion (HME) is widely used to prepare polymer-based solid dispersions (SDs), but evaluating trace water-related changes in HME-prepared SDs remains challenging. In this study, time-domain NMR (TD-NMR) was applied to clotrimazole/Polyvinylpyrrolidone-co-vinyl acetate (PVPVA) SDs prepared by HME to evaluate T₂ relaxation behavior associated with low water content. The water content was determined by Karl Fischer titration and thermogravimetry-differential thermal analysis. T₂ relaxation curves were obtained by TD-NMR and analyzed using curve-fitting analysis and partial least squares (PLS) regression. Characteristic oscillatory behavior was observed in the T₂ relaxation curves of the low-moisture samples. Fitting analysis using a Gaussian function with an offset term showed that the offset ratio was associated with the water content measured by both methods. PLS regression analysis using the signal intensities constituting the T₂ relaxation curves as input variables predicted the Karl Fischer water content with relatively good accuracy. The analysis of variable importance in projection, which evaluates the contribution of each input variable to the PLS model, indicated that the time region of the T₂ relaxation curve contributing to the prediction corresponded to the region where oscillatory relaxation behavior was observed. These findings suggest that the oscillatory T₂ relaxation behavior was associated with water content within the present sample set and may reflect markedly restricted molecular mobility under low-moisture conditions, indicating that TD-NMR may be useful as a nondestructive approach for evaluating water-related physical property changes in the HME-prepared clotrimazole/PVPVA SDs.